2,3-Dihydro-6,7-disubstituted-5-acyl benzofuran-2-carboxylic acids

ABSTRACT

2,3-Dihydro-6,7-disubstituted-5-(acyl)benzofuran-2-carboxylic acids, the pharmaceutically acceptable salt, ester and amide derivatives thereof and combinations of these compounds with antikaluretic agents are disclosed having diuretic-saluretic, uricosuric and antihypertensive activity.

BACKGROUND OF THE INVENTION

This case is a continuation-in-part of our earlier filed case U.S.application Ser. No. 594,839, filed in the U.S. Patent Office on July 9,1975 now abandoned.

This invention relates to certain benzofurans having diuretic-saluretic,uricosuric and antihypertensive pharmacological activity. Further, thisinvention relates to processes for the preparation of such compounds;pharmacological compositions comprising such compounds; and to methodsof treatment comprising administering such compounds and compositions topatients (both human and animal) for the alleviation of symptomsassociated with electrolyte imbalance and fluid retention such as edemaassociated with hypertension.

The compounds of this invention may be represented by the followinggeneric structure: ##STR1## wherein X is halo (chloro, fluoro, bromo oriodo) methyl or hydrogen;

Y is halo (chloro, fluoro, bromo or iodo) or methyl;

X and Y can be joined to form a hydrocarbylene chain containing from 3to 4 carbon atoms, for example: 1,3-butadienylene:

R is aryl such as phenyl or mono or disubstituted phenyl wherein thesubstituent is halo, methyl, trifluoromethyl or methoxy; aralkyl such asbenzyl or mono or dinuclear substituted aralkyl wherein the substituentis halo, methyl, methoxy or trifluoromethyl; or a heterocyclic groupsuch as a 5 or 6 membered heterocyclic ring containing one or more atomsof oxygen, sulfur or nitrogen such as 3- or 2-thienyl, 3 or 2-furyl,1,2,5-thiadiazolyl or substituted heterocyclics as above wherein thesubstituent is halo or methyl.

Also within the scope of the present invention are the pharmaceuticallyacceptable salt, ester and amide derivatives of the above describedcompounds.

For convenience, these compounds will be collectively referred to as"dihydrobenzofuran acids."

The pharmacological studies show that the instant products are effectivediuretic, saluretic and uricosuric agents which can be used in thetreatment of conditions associated with electrolyte and fluid retentionin the treatment of hypertension. These compounds are able to maintainthe uric acid concentration in the body at pretreatment levels or toeven effect a decrease in the uric acid concentration when administeredin therapeutic dosages in conventional vehicles.

Many of the presently available diuretics and saluretics have a tendencyupon administration to induce hyperuricemia which may precipitate uricacid or sodium urate or both in the body which may cause from mild tosevere cases of gout. The instant compounds of this invention nowprovide an effective tool to treat those patients (which includes humansand animals) requiring diuretic and saluretic treatment withoutincurring the risk of inducing gout. In fact, when used in appropriatedoses, the compounds of this invention function as uricosuric agents.

Thus it is an object of the present invention to provide the benzofuransof the above general description and to provide processes forpreparation of such compounds. Further objects of this invention are toprovide pharmaceutical compositions comprising such benzofurans and toprovide methods of treatment comprising administering such compounds andcompositions.

DETAILED DESCRIPTION OF THE INVENTION

For purposes of description, the benzofurans of the present invention(Formula I above) may be represented according to the followingstructural formula: ##STR2## wherein X, Y and R are as previouslydefined.

The preferred benzofurans of the present invention are those compoundsof Formula I wherein X is halo, preferably chloro, or methyl and Y ishalo, preferably chloro or methyl, and the pharmaceutically acceptablesalts, ester and amide derivatives thereof.

More preferred benzofurans of the present invention are those preferredcompounds of Formula I wherein R is ##STR3## and X and Y are as definedabove.

Still more preferred benzofurans of the present invention are thosecompound of Formula II below ##STR4## wherein X is chloro and

Y is chloro, and

R is as defined for the more preferred benzofurans above, and thepharmacologically acceptable salts, ester and amide derivatives thereof.

A still more preferred aspect of the invention are those compounds ofFormula II wherein X and Y are both chloro and R is ##STR5## and thepharmaceutically acceptable salts, ester and amide derivatives thereof.

Several examples of specific compounds of this invention are6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid;

6,7-dichloro-2,3-dihydro-5-(2-furoyl)benzofuran-2-carboxylic acid;

6,7-dichloro-2,3-dihydro-5-(5-methyl-2-thenoyl)benzofuran-2-carboxylicacid;

6,7-dichloro-2,3-dihydro-5-(3-thenoyl)benzofuran-2-carboxylic acid;

6,7-dichloro-2,3-dihydro-5-(3-furoyl)benzofuran-2-carboxylic acid;

6,7-dichloro-2,3-dihydro-5-(5-methyl-2-furoyl)benzofuran-2-carboxylicacid;

6,7-dichloro-2,3-dihydro-5-(1,2,5-Thiadiazol-3-yl)-benzofuran-2-carboxylicacid;

6,7-dichloro-2,3-dihydro-5-benzoylbenzofuran-2-carboxylic acid;

6,7-dichloro-2,3-dihydro-5-(p-methoxyphenylacetyl)benzofuran-2-carboxylicacid.

The preferred groups of compounds depicted above have especially gooddiuretic, saluretic, uricosuric and antihypertensive pharmacologicalactivity.

The benzofurans of the present invention may be prepared essentially bythe reaction scheme shown below: ##STR6## wherein X, Y and R are asdefined, Z is halo and R² is lower alkyl (C₁₋₄).

In this reaction scheme, a 2,3-disubstituted-phenol (III) is treatedwith allyl bromide to yield the corresponding allyl ether (V). Typicallythe allyl bromide is employed in excess; in fact it may serve as thereaction solvent. Other solvents, provided they are compatible with thedesired course of reaction may be employed, for example, ethanol,dimethylformamide and the like. Typically the reaction is conducted inthe presence of a base such as sodium alkoxide, potassium carbonate andthe like at a temperature in the range of from about 25° to about 100°C. and is substantially complete in from about 0.5 to about 2 hours. TheClaisen rearrangement to obtain the 6 allyl compound (Formula VI) iseffected by heating the reaction mixture at from about 100° to 220° C.The benzofuran nucleus (VIII) is obtained from the 4-allyl compound (VI)by treatment with a peracid such as m-chloroperbenzoic, peracetic acidand the like in a solvent such as methylene chloride, chloroform, aceticacid and the like at a temperature of from about 0° C. to the refluxtemperature of the solvent wherein the epoxide (VII) which is initiallyformed cyclizes to (VIII). There are brackets around the epoxide ofFormula VII to indicate that it is most generally not isolated and is anintermediate in this particular reaction step. Oxidation of theresulting hydroxymethyl-substituted-benzofuran (VII) yields thebenzofurancarboxylic acid (IX).

Typically this oxidation is effected by oxidizing agents such as chromicacid, potassium permanganate and the like; the temperature of thereaction being typically in the range of from about 0° C. to the refluxtemperature of the solvent which is used.

The solvent can be any inert solvent that is not effected by thereaction.

Finally the benzofurancarboxylic acid compound (Formula IX) is convertedto the dihydrobenzofurancarboxylic acid compounds of the instantinvention (Formula I) by reacting said compound Formula IX or its loweralkyl (C₁₋₄) ester X under Friedel-Crafts conditions with a carboxylicacid halide of the formula: RCOZ wherein R has been previously definedand Z is halogen such as chloro or bromo, to yield the desired productdirectly or by hydrolysis of the resultant ester XI. The lower alkylester X can be prepared from the acid IX by known esterificationprocedures. Suitable catalysts for the Friedel-Crafts type reaction oncompounds of Formula IX are aluminum chloride, tin (IV) tetrachlorideand the like. The reaction solvent and temperature are not criticalinasmuch as any solvent which is inert to the acyl halide/benzofuranreactants may be employed. In this regard, suitable solvents includealiphatic and cycloaliphatic hydrocarbons such as heptane, cyclohexane,and the like; nitrohydrocarbons such as nitrobenzene and the like; andhalogenated hydrocarbons such as carbon tetrachloride, methylenechloride, and the like are employable. The reaction is generally rununtil formation of the desired product (I) is complete, preferably fromabout 1 to 6 hours.

Typically the reaction is conducted from 0° C. to the reflux temperatureof the particular solvent employed but temperatures up to about 100°maximum may be employed. Applicants have found that a better yield offinal product (I) is obtained from compound IX by using no inert solventbut using a slight excess of the acyl halide.

As previously mentioned, the nontoxic, pharmacologically acceptablesalts of the acids of Formula I and II are within the scope of thisinvention. These salts include those of alkali metals, alkaline earthmetals and mines such as ammonia, primary and secondary amines andquaternary ammonium hydroxides. Especially preferred metal cations arethose derived from alkali metals, e.g., sodium, potassium, lithium, andthe like and alkaline earth metals, e.g., calcium, magnesium, and thelike and other metals, e.g., aluminum, iron and zinc.

Pharmaceutically acceptable salts can be formed from ammonia, primary,secondary, or tertiary amines, or quaternary ammonium hydroxides such asmethylamine, dimethylamine, trimethylamine, ethylamine,N-methylhexylamine, benzylamine, α-phenethylamine, ethylenediamine,piperidine, 1-methylpiperazine, morpholine, pyrrolidine,1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine,tris(hydroxymethyl)aminomethane, N-methylglucamine, N-methylglucosamine,ephedrine, procaine, teramethylammonium hydroxide, tetrethylammoniumhydroxide, benzyltrimethylammonium and the like. These salts areparticularly useful as parenteral solutions because they are verysoluble in pharmaceutical carriers such as water or alcohol.

Also included within the scope of this invention are the ester and amidederivatives of the instant products which are prepared by conventionalmethods well known to those skilled in the art. Thus, for example, theester derivative may be prepared by the reaction of andihydrobenzofuran-2-carboxylic acid of this invention with an alcohol,for example, with a lower alkanol such as methanol or ethanol. The amidederivatives may be prepared by converting the same acid to itscorresponding acid chloride by treatment with thionyl chloride followedby treating said acid chloride with ammonia, an appropriate mono-loweralkylamine, di-lower alkyl amine or a hetero amine, such as piperidine,morpholine and the like, to produce the corresponding amide compound.These and other equivalent methods for the preparation of the ester andamide derivatives of the instant products will be apparent to one havingordinary skill in the art and to the extent that said derivatives areboth non-toxic and physiologically acceptable to the body system, saidderivatives are the functional equivalent of the corresponding freeacids of the present invention.

Of the non-toxic pharmaceutically acceptable salt, ester and amidederivatives of Formulae I and II, the preferred salts are those ofammonia, amines and of the alkali metals -- principally sodium andpotassium; the preferred esters are those derived from lower alkanolshaving from 1 to about 6 carbon atoms; the preferred amides are thosederived from mono- and di-lower alkyl amines and hetero amines such aspiperidine, morpholine and the like.

The instant compounds disclosed herein contain asymmetric carbon atom atposition 2 of the benzofuran ring. The enantiomers may be separated bymethods well known to those skilled in the art. This invention,therefore, embraces not only the racemic benzofurans but also theoptically active enantiomers. In general, the pure enantiomers areprepared by fractional crystallization of salts of the racemic acidsderived from optically active amines followed by generation of the freeacid of the enantiomer by addition of an equimolar amount of a strongacid such as hydrochloric acid. Several specific isomers are (+)6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid and(-) 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid.

Unexpectedly, the ratio of the two pharmacodynamic activities, i.e.,saluretic-diuretic and uricosuric, is not necessarily the same in eachenantiomer. In fact, in some instances, one property lies almostentirely in the (+)-enantiomer while the other lies in the(-)-enantiomer. For example, racemic6,7-dichloro-2,3-dihydro-5-(2-Thenoyl)benzofuran-2-carboxylic acidexhibits both potent saluretic-diuretic and uricosuric activity. The(+)-enantiomer possesses marked saluretic-diuretic activity with verylittle uricosuric effects while the reverse is true for the(-)enantiomer. This unique situation permits a selection of any desiredratios of the two properties by selection of the appropriate ratio ofthe two enantiomers. For example when various isomeric ratios of the twoenantiomers of6,7-dichloro-2,3-dihydro-5-(2-Thenoyl)-benzofuran-2-carboxylic areadministered orally to chimpanzees in a total dose of 5 mg./kg., thefollowing observations are made.

    ______________________________________                                        % of Isomer                                                                   +           -       saluresis-diuresis                                                                         Uricosuric                                   ______________________________________                                                100      0      very marked                                                                              marginal                                           75      25      very marked                                                                              weak                                       (racemate)                                                                            50      50      marked     modest                                             25      75      good       strong                                               12.5    87.5  modest     marked                                              0      100     marginal   very marked                                ______________________________________                                    

Although diuretics are often life-saving because of the above beneficialtherapeutic effects, most of them have the disadvantage of causing theexcretion of appreciable amounts of potassium ions. When an excessiveloss of potassium ions occurs, a severe muscular weakness and feeling ofextreme physical exhaustion results. The patient eliminates the unwantedsodium ions due to the action of the diuretic drugs but the undesiredelimination of the potassium ions produces an imbalance that should notbe allowed to persist.

This invention also involves co-administration of adihydrobenzofurancarboxylic acid with a pyrazinoylguanidine either inthe form of a salt and/or as a mixture with a hydrochloride salt ofpyrazinoylguanidine, to thereby prevent the elimination of excessiveamount of potassium ions without altering or actually increasing theamount of sodium ions that are eliminated.

To achieve the beneficial results of this invention, the preferredpyrazinoylguanidine compound isN-amidino-3,5-diamino-6-chloropyrazinecarboxamide (amiloride) or itshydrochloride salt (amiloride hydrochloride) which is described in theliterature and patented arts.

Another advantage of theN-amidino-3,5-diamino-6-chloropyrazinecarboxamide salts of thedihydrobenzofurancarboxylic acid diuretics is their insolubility whichmakes the salts' gastrointestinal absorption slower and more gradualproviding a chemical method of achieving the same effect asmicroencapsulation.

The examples which follow illustrate the benzofuran products of thepresent invention and the methods by which they are prepared. However,the examples are illustrative only and it will be apparent to thosehaving ordinary skill in the art that all the products embraced by theabove-given description of the present invention may also be prepared inan analogous manner by substituting the appropriate starting materialsfor those set forth in the examples.

EXAMPLE 1(±)6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid

Step A: 2,3-Dichloro-6-allylphenol

A mixture of 2,3-dichlorophenol (35.5 g., 0.22 mole), allyl bromide(29.4 g., 0.24 mole) and potassium carbonate (33 g., 0.24 mole) indimethylformamide (200 ml.) is vigorously stirred and heated at 55°-60°C. for 1 hour, poured into ice water, extracted with ether, washed withwater and dried over magnesium sulfate. Evaporation of the ether leaves2,3-dichlorophenyl allyl ether which is subjected to a Claisenrearrangement by heating at 250° C. for 10 minutes. Distillation gives36 g. of 2,3-dichloro-6-allylphenol which boils at 132°-134°/13 mm.

Elemental analysis for C₉ H₈ Cl₂ O; Calc.: C, 53.23; H, 3.97; Found: C,52.37; H, 3.86.

Step B: 6,7-Dichloro-2,3-dihydro-2-hydroxymethylbenzofuran

A stirred solution of sodium acetate (1 g.) in 40% peracetic acid (25ml.) is cooled to 15° C. then treated dropwise with2,3-dichloro-6-allylphenol. The reaction mixture is stirred at 25° C.for 48 hours, poured into excess aqueous sodium bicarbonate, extractedinto ether, washed with aqueous sodium bicarbonate, water, aqueousferrous sulfate, water, brine and dried over magnesium sulfate.Evaporation of the ether leaves 2,3-dichloro-6-(2,3-epoxypropyl)phenolwhich is rearranged by heating at 110° C. for 10 minutes then distilledto give 10.4 g. of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuranwhich boils at 130°/0.1 mm.

Elemental analysis for C₉ H₈ Cl₂ O₂ ; Calc.: C, 49.34; H, 3.68; Found:C, 49.67; H, 3.74.

Step C: 6,7-Dichloro-2,3-dihydrobenzofuran-2-carboxylic acid

To a solution of 6,7-dichloro-2,3-dihydro-2-hydroxymethylbenzofuran(10.4 gm.) in acetone (200 ml.) cooled to 20° C. is added an oxidizingsolution prepared from chromium trioxide (6.0 g.), concentrated sulfuricacid (5.3 ml.) and water (43 ml.) over a one-half hour period. Thereaction mixture is stirred at 25° C. for 18 hours. The acetone layer isseparated from the precipitated chromium salts, added to water (600 ml.)and extracted with ether (2 × 150 ml.). The ether extract is washed withwater then extracted with aqueous sodium bicarbonate. Acidification ofthe basic solution gives 3.4 g. of6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid which is purifiedby reprecipitation from aqueous sodium hydroxide with aqueoushydrochloric acid.

Elemental analysis for C₉ H₆ Cl₂ O₃ ; Calc.: Cl, 30.43; Found: Cl,30.29.

Step D: (±)6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylicacid

To a well stirred mixture of6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (2.6 g.) andthiophene-2-carbonyl chloride (4 ml.) protected from the atmosphere witha calcium chloride tube is added anhydrous aluminum chloride (6.0 g.)over a 1-hour period. The reaction mixture is heated at 80°-90° C. for31/2 hours then poured into ice water (100 ml.) and hydrochloric acid(10 ml.). The product is extracted into ether, washed with water, thenextracted into aqueous sodium bicarbonate (100 ml.) from which thesodium salt of the product precipitates. The sodium salt of the productis placed in a separatory funnel with dilute hydrochloric acid (100 ml.)and ether (100 ml.) and shaken until the solid dissolves. The ethersolution is washed with water, brine, dried over magnesium sulfate andthe ether distilled at reduced pressure. The(±)6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acidmelts at 187° C. after crystallization from butyl chloride.

Elemental analysis for C₁₄ H₈ Cl₂ O₄ S; Calc.: C, 49.00; H, 2.35; Found:C, 48.72, H, 2.56.

EXAMPLE 2(±)6,7-Dichloro-2,3-dihydro-5-(2-furoyl)benzofuran-2-carboxylic acid

To a well stirred mixture of6,7-dichloro-2,3-dihydro-benzofuran-2-carboxylic acid (3.3 g.),furan-2-carbonyl-chloride (3.6 g.) and 200 ml. methylene chloride,protected from the atmosphere with a calcium chloride tube is addedanhydrous aluminum chloride (3.7 g.) over a one-half hour period. Thereaction solution is stirred 18 hours at 25° C. and then refluxed for 1hour. The solvent is removed and the residue added to ice water (200ml.) and hydrochloric acid (20 ml.). The product is extracted intoether, washed with water, then extracted into aqueous sodium bicarbonate(200 ml.) from which the sodium salt of the product precipitates. Thesodium salt of the product is placed in a separatary funnel with dilutehydrochloric acid (100 ml.) and ether (100 ml.) and shaken until thesolid dissolves. The ether solution is washed with water, brine, driedover magnesium sulfate and the ether distilled at reduced pressure. The6,7-dichloro-2,3-dihydro-5-(2-furoyl)benzofuran-2-carboxylic acid meltsat 166° C after crystallization from acetonitrile/n-butyl chloride.

Elemental analysis for C₁₄ H₈ Cl₂ O₅ ; Calc.: C, 51.40; H, 2.46; Found:C, 51.59; H, 2.72.

EXAMPLE 36,7-Dichloro-2,3-dihydro-5-[3-(1,2,5-Thiadiazolyl)]benzofuran-2-carboxylicacid

Step A: 6,7-Dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester

A solution of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (70g.) conc. sulfuric acid (2 ml.) and ethanol (250 ml.) is refluxed for 2hours. The ethanol is distilled at reduced pressure and the residue issuspended in saturated sodium bicarbonate and extracted with ether. Theether solution is washed with brine, dried over magnesium sulfate andthe ether distilled at reduced pressure. The6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester is usedwithout further purification in the following synthesis.

Step B:6,7-Dichloro-2,3-dihydro-5-[3-(1,2,5-Thiadiazolyl)]benzofuran-2-carboxylicacid

To a well stirred mixture of6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (17.5g.) and 1,2,5-thiadiazole-3-carbonyl chloride (21.7 g.) protected fromthe atmosphere with a calcium chloride tube is added the anhydrousaluminum chloride (29.4 g.) over a one-half hour period. The reactionmixture is heated at 90°-95° C for 6 hours, then poured into ice water(400 ml.) and hydrochloric acid (40 ml.). The esterified product isextracted into ether, washed with water, dried over magnesium sulfateand the ether distilled at reduced pressure. The residue was warmed (80°C.) in 2.0 N NaOH (100 ml.) for 1 hour to obtain the insoluble sodiumsalt of the product. The sodium salt of the product is placed in aseparatory funnel with dilute hydrochloric acid (250 ml.) and ether (500ml.) and shaken until the solid dissolves. The ether solution is washedwith water, brine, dried over magnesium sulfate and the ether isdistilled at reduced pressure. The 6,7-dichloro-2,3-dihydro-5-[3-(1,2,5-Thiadiazolyl)]benzofuran-2-carboxylicacid melts at 188° C after recrystallization from acetonitrile.

Elemental analysis for C₁₂ H₆ Cl₂ N₂ O₄ S; Calc.: C, 41.75; H, 1.75; N,8.12; Found: C, 41.77; H, 1.89, N, 8.06.

EXAMPLE 4

Starting with (±)6,7-dichloro-2,3-dihydro-benzofuran-2-carboxylic acidbut substituting equimolar amounts of the following acyl halides inplace of thiophene-2-carbonyl chloride in step D of Example 1 andfollowing the procedure of Step D there is obtained a correspondingamount of the appropriate end product listed.

    ______________________________________                                        ACID CHLORIDE   END PRODUCT                                                   ______________________________________                                        5-methylthiophene-2-                                                                          (±)6,7-dichloro-2,3-dihydro-5-                             carbonyl chloride                                                                             (5-methyl-2-thenoyl)benzofuran-                                               2-carboxylic acid                                             thiophene-3-carbonyl                                                                          (±)6,7-dichloro-2,3-dihydro-5-                             chloride        (3-thenoyl)benzofuran-2-                                                      carboxylic acid                                               furan-3-carbonyl chloride                                                                     (±)6,7-dichloro-2,3-dihydro-5-                                             (3-furoyl)benzofuran-2-                                                       carboxylic acid                                               5-methylfuran-2-carbonyl                                                                      (±)6,7-dichloro-2,3-dihydro-5-                             choride         (5-methyl-2-furoyl)benzofuran-2-                                              carboxylic acid                                               ______________________________________                                    

EXAMPLE 5

Where in Example 1, Step D, there is substituted for the(±)6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid an equivalentamount of (±)2,3-dihydro-6,7-dimethylbenzofuran-2-carboxylic acid,(±)2,3-dihydro-6-methylbenzofuran-2-carboxylic acid,(±)6-chloro-2,3-dihydrobenzofuran-2-carboxylic acid or(±)6-chloro-2,3-dihydro-7-methylbenzofuran-2-carboxylic acidrespectively, the following compounds of this invention are obtained,respectively:

(±)2,3-dihydro-6,7-dimethyl-5-(2-thenoyl)benzofuran-2-carboxylic acid;

(±)2,3-dihydro-6-methyl-5-(2-thenoyl)benzofuran-2-carboxylic acid;

(±)6-chloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid;

(±)6-chloro-2,3-dihydro-7-methyl-5-(2-thenoyl)benzofuran-2-carboxylicacid.

EXAMPLE 66,7-Dichloro-2,3-dihydro-5(4-methoxybenzoyl)benzofuran-2-carboxylic acid

Following the procedure of Example 2 but using an equivalent amount ofanisoyl chloride in place of furan-2-carbonyl chloride used in Example2, there is produced an equivalent amount of6,7-Dichloro-2,3-dihydro-5-(4-methoxybenzoyl)benzofuran-2-carboxylicacid.

M.P. = 187° C

Elemental analysis for C₁₇ H₁₂ Cl₂ O₅ ; Calc.: C, 55.60; H, 3.29; Cl,19.31; Found: C, 55.67; H, 3.35; Cl, 18.99.

EXAMPLE 7 6,7-Dichloro-2,3-dihydro-5-phenylacetylbenzofuran-2-carboxylic acid

Following the procedure of Example 3B but using an equivalent amount ofphenyl acetyl chloride in place of 1,2,5-thiadiazole-3-carbonyl chorideand using carbon disulfide as a solvent there is produced an equivalentamount of 6,7-Dichloro-2,3-dihydro-5-phenyl acetylbenzofuran-2-carboxylic acid.

M.P. = 146° C

Elemental analysis for C₁₇ H₁₂ Cl₂ O₄ ; Calc.: C, 58.14; H, 3.44; Found:C, 58.12; H, 3.67.

EXAMPLE 8 Resolution of the Optical Isomers of(±)6,7-Dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid

Step A: (+)-isomer

A mixture of racemic6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-benzofuran-2-carboxylic acid(28.0 g., 0.081 mole) and (-)-cinchonidine (24.0 g., 0.081 mole) isdissolved in hot acetonitrile (1500 ml.) and aged at 25° C. for 18hours.

The acetonitrile is decanted from the resultant salt (28.7 g.) which isrecrystallized twice from a minimum volume of acetonitrile and twicefrom a minimum volume of 95% ethanol affording 15.7 g. of salt of thepure (+)-enantiomer which is converted to the acid by treatment of thesalt with dilute hydrochloric acid and ether. The ether phase is washedwith water, dried over magnesium sulfate, and the ether distilled atreduced pressure to give the (+)-isomer.

[α]₄₃₆ ²⁵ = + 11.5 (C, 1, acetone)

Step B: (-)-isomer

By following substantially the procedure described in Step A, thepartially resolved6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-benzofuran-2-carboxylic acid(12.0 g., 0.035 mole); (obtained from acetonitrile mother liquor of stepA) and (+)-α-methylbenzylamine (4.3 g., 0.035 mole) are mixed inacetonitrile (1000 ml.). The resultant salt (14.5 g.) was thricerecrystallized from a minimum volume of acetonitrile and ethanol (10:1)to obtain 9.4 g. of the salt of the pure (-)-enantiomer which isconverted to the acid by treatment of the salt with dilute hydrochloricacid and ether.

[α]₄₃₆ ²⁵ = - 11.5 (C, 1, acetone)

As mentioned previously, the novel compounds of this invention arediuretic and saluretic agents. When administered to patients intherapeutic dosages in conventional vehicles, the instant productseffectively reduce the amount of sodium and chloride ions in the body,lower dangerous excesses of fluid levels to acceptable levels and ingeneral, alleviate conditions usually associated with edema or fluidretention.

Also as mentioned previously, these compounds are able to maintain theuric acid concentration in the blood at pretreatment levels or evencause a decrease in uric acid concentration. The presence of excess uricacid in the blood can lead to crystallization of uric acid and uric acidsalts in the joints causing gout. In addition hyperuricemia inconjunction with hyperlipidemia has been implicated in increasing therisk of sustaining cardiovascular heart disease.

The compounds of this invention can be administered to patients (bothanimal and human) as the racemic form, as either enantiomer or in a widevariety of mixtures of various ratios of the two enantiomers, each ofwhich may be given in any of a variety of therapeutic dosages inconventional vehicles as, for example, by oral administration in theform of a tablet or by intravenous injection. In addition, the compoundsmay be formulated into suppositories or as a salve for topicaladministration or they may be administered sublinqually. Also, the dailydosage of the products may be varied over a wide range as for example,in the form of scored tablets containing 0.25, 1, 5, 10, 25, 50, 100,150, 200, 250 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thesedosages are well below the toxic or lethal dose of the products.

A suitable unit dosage form of the product of this invention can beadministered by mixing 25 mg. of a dihydrobenzofuran or a suitable salt,ester or amide derivative thereof of the present invention with 174 mg.of lactose and 1 mg. of magnesium stearate and placing the 200 mg.mixture into a No. 1 gelatin capsule. Similarly by employing more of theactive ingredient and less lactose, other dosage forms can be put up inNo. 1 gelatin capsules and should it be necessary to mix more than 200mg. of ingredients together larger capsules may be employed. Compressedtablets, pills or other desired unit dosages can be prepared toincorporate the compounds of this invention by conventional methods andif desired can be made up as elixirs or as injectable solutions bymethods well known to pharmacists.

An effective amount of the product is ordinarily supplied at a unitdosage level of from about 0.003 mg. to about 10 mg./kg. of body weightof the patient. Preferably the range is from about 0.01 mg. to about 1.5mg./kg. with a most preferred dose being about 0.07 to 0.35 mg./kg. ofbody weight. The unit dose can be administered as infrequently as twiceper week to as frequently as 3 times per day.

It is also within the scope of this invention to combine two or more ofthe compounds of this invention into a unit dosage form or to combineone or more of the compounds of this invention with other knowndiuretics and saluretics or with other desired therapeutic and/ornutritive agents in dosage unit form.

The present invention embraces such compositions administration topatients, preferably by oral administration, wherein the potassiumconserving diuretic, N-amidino-3,5-diamino-6-chloropyrazinecarboxamidehydrochloride, hereinafter referred to as amiloride hydrochloride, ispresent as a physical mixture in combination with the dihydrobenzofuransof the present invention. The present invention embraces compositionswherein the molar ratio of the dihydrobenzofuran to amiloridehydrochloride ranges from about 50:1 to 1:1. The preferred ratios of thedihydrobenzofuran to amiloride hydrochoride ranges from 25:1 to 1:1.

EXAMPLE 9

    ______________________________________                                        Dry-filled capsules containing 25 mg. of active ingredients                   per capsule                                                                                       Per Capsule                                               ______________________________________                                        (±)6,7-Dichloro-2,3-dihydro-5-(2-                                                                 25 mg.                                                 thenoyl)-benzofuran-2-carboxylic                                              Lactose               174 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No.1)   200 mg.                                                 ______________________________________                                    

The (±)6,7-dichloro-2,3-dihydro-5-(2-thenoyl)-benzofuran-2-carboxylicacid is reduced to a No. 60 powder and then lactose and magnesiumstearate are passed through a No. 60 bolting cloth onto the powder andthe combined ingredients admixed for 10 minutes and then filled into aNo. 1 dry gelatin capsule.

Similar dry-filled capsules are prepared by replacing the activeingredient of the above example by the sodium, diethanolamine, andtriethanolamine salt thereof, respectively.

Similarly dry filled capsules can be prepared by replacing the activeingredient of the above example by a molar equivalent amount of any ofthe other novel compounds of this invention.

EXAMPLES 10-16

Following the procedure for combining the ingredients as described inExample 9, the following dry filled capsules can be prepared.

Similar dry filled capsules can be prepared by replacing the benzofuranactive ingredient of the above examples by the sodium, diethanol amineand triethanolamine salts thereof, respectively. Also dry filledcapsules can be prepared by replacing the benzofuran active ingredientof the above examples by a molar equivalent of any of the othercompounds of this invention.

EXAMPLE 10

    ______________________________________                                        Dry-filled capsules containing 15 mg. of active ingredient                    per capsule                                                                                       Per Capsule                                               ______________________________________                                        (+)-6,7-Dichloro-2,3-dihydro-5-(2-                                                                   15 mg.                                                 thenoyl)benzofuran-2-carboxylic acid                                          Lactose               184 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

EXAMPLE 11

    ______________________________________                                        Dry-filled capsules containing 45 mg. of active ingredients                   per capsule                                                                                       Per Capsule                                               ______________________________________                                        (+)6,7-Dichloro-2,3-dihydro-5-(2-                                             thenoyl)benzofuran-2-carboxylic acid                                                                 15 mg.                                                 (-)6,7-Dichloro-2,3-dihydro-5-(2-                                             thenoyl)benzofuran-2-carboxylic acid                                                                 30 mg.                                                 Lactose               159 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

EXAMPLE 12

    ______________________________________                                        Dry-filled capsules containing 40 mg. of active ingredients                   per capsule                                                                                       Per Capsule                                               ______________________________________                                        (+)-6,7-Dichloro-2,3-dihydro-5-(2-                                            thenoyl)benzofuran-2-carboxylic acid                                                                 10 mg.                                                 (-)6,7-Dichloro-2,3-dihydro-5-(2-                                             thenoyl)benzofuran-2-carboxylic acid                                                                 30 mg.                                                 Lactose               159 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

EXAMPLE 13

    ______________________________________                                        Dry-filled capsules containing 50 mg. of active ingredients                   per capsule                                                                                       Per Capsule                                               ______________________________________                                        (±)6,7-dichloro-2,3-dihydro-5-(2-                                          thenoyl)benzofuran-2-carboxylic acid                                                                 20 mg.                                                 (-)6,7-Dichloro-2,3-dihydro-5-(2-                                             thenoyl)benzofuran-2-carboxylic acid                                                                 30 mg.                                                 Lactose               149 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

EXAMPLE 13

    ______________________________________                                        Dry-filled capsules containing 50 mg. of active ingredients                   per capsule                                                                                       Per Capsule                                               ______________________________________                                        (±)6,7-Dichloro-2,3-dihydro-5-(2-                                          thenoyl)benzofuran-2-carboxylic acid                                                                 20 mg.                                                 (-)6,7-Dichloro-2,3-dihydro-5-(2-                                             thenoyl)benzofuran-2-carboxylic acid                                                                 30 mg.                                                 Lactose               149 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

EXAMPLE 14

    ______________________________________                                        Dry-filled capsules containing 25 mg. of active ingredient                    per capsule                                                                                       Per Capsule                                               ______________________________________                                        6,7-Dichloro-2,3-dihydro-5-(2-                                                furoyl)benzofuran-2-carboxylic acid                                                                  25 mg.                                                 Lactose               179 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

EXAMPLE 15

    ______________________________________                                        Dry-filled capsules containing 20 mg. of dihydrobenzofuran                    and 5 mg. of amiloride hydrochloride dihydrate per capsule                                        Per Capsule                                               ______________________________________                                        (±)6,7-Dichloro-2,3-dihydro-5-(2-                                          thenoyl)benzofuran-2-carboxylic acid                                                                 20 mg.                                                 N-amidino-3,5-diamino-6-chloropyrazine-                                       carboxamide hydrochloride dihydrate                                                                  5 mg.                                                  Lactose               174 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

EXAMPLE 16

    ______________________________________                                        Dry-filled capsules containing 40 mg. of dihydrobenzofuran                    and 5 mg. of amiloride hydrochloride dihydrate per capsule                                        Per Capsule                                               ______________________________________                                        (±)6,7-Dichloro-2,3-dihydro-5-(2-                                          thenoyl)benzofuran-2-carboxylic acid                                                                 20 mg.                                                 (±)6,7-Dichloro-2,3-dihydro-5-)2-                                          thenoyl)benzofuran-2-carboxylic acid                                                                 20 mg.                                                 N-amidino-3,5-diamino-6-chloropyrazine-                                       carboxamide hydrochloride dihydrate                                                                  5 mg.                                                  Lactose               154 mg.                                                 Magnesium stearate     1 mg.                                                  Capsule (Size No. 1)  200 mg.                                                 ______________________________________                                    

What is claimed is:
 1. A compound having the formula: ##STR7## wherein Xis halo, methyl or hydrogen;Y is halo or methyl and R is 2-thienyl,3-thienyl or 2 or 3 substituted thienyl wherein the substituent is haloor methyl, a non-toxic pharmaceutically acceptable salt and a loweralkyl ester derivative thereof.
 2. A compound of claim 1 wherein X ishalo or methyl and Y is halo or methyl.
 3. A compound of claim 2 whereinX and Y are halo.
 4. A compound of the formula ##STR8## wherein X ishalo, methyl or hydrogen;Y is halo or methyl; R is selected from thegroup consisting of 2-thienyl, 3-thienyl and 5-methyl-2-thienyl,anon-toxic pharmaceutically acceptable salt thereof or a lower alkylester derivative thereof.
 5. The compound of claim 4 wherein X and Y areboth chloro.
 6. The (+) and (-) isomers of the compound of claim
 5. 7.The compound of claim 1 wherein X and Y are chloro and R is 2-thienylthus forming6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid. 8.The (+) enantiomer of the compound of claim
 7. 9. The (-) enantiomer ofthe compound of claim
 7. 10. A mixture of 1 part (+) enantiomer of thecompound of claim 8 with 2 to 4 parts of the (-) enantiomer of thecompound of claim
 7. 11. The compound of claim 1 wherein X and Y aremethyl and R is 2-thienyl thus forming2,3-dihydro-6,7-dimethyl-5-(2-thenoyl)benzofuran-2-carboxylic acid. 12.The compound of claim 1 wherein X is hydrogen and Y is chloro, and R is2-thienyl thus forming6-chloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid.
 13. Thecompound of claim 1 wherein X and Y are chloro and R is 2-methylthienylthus forming6,7-dichloro-2,3-dihydro-5-(5-methyl-2-thenoyl)benzofuran-2-carboxylicacid.
 14. The compound of claim 1 wherein X is methyl and Y is chloroand R is 2-thienyl thus forming6-chloro-2,3-dihydro-7-methyl-5-(2-thenoyl)benzofuran-2-carboxylic acid.15. A pharmaceutical composition useful in the treatment of edema andhypertension comprising a therapeutically effective amount of a compoundof the formula of ##STR9## wherein X is halo, methyl or hydrogen;Y ishalo or methyl; R is 2-thienyl, 3-thienyl or 2 or 3 substituted thienylwherein the substituent is halo or methyl,a non-toxic pharmaceuticallyacceptable salt thereof or a lower alkyl ester derivative thereof and apharmaceutically acceptable carrier.
 16. A pharmaceutical compositionaccording to claim 15 wherein X and Y are both chloro.
 17. Apharmaceutical composition useful in the treatment of edema andhypertension comprising a therapeutically effective amount of a compoundof the formula: ##STR10## wherein X is chloro;Y is chloro; and R isselected from the group consisting of 2-thienyl, 3-thienyl and5-methyl-2-thienyl, a non-toxic pharmaceutically acceptable salt thereofor a lower alkyl ester derivative thereof and a pharmaceuticallyacceptable carrier.
 18. A pharmaceutical composition of claim 17 whereinthe said compound is6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid. 19.A pharmaceutical composition of claim 18 wherein the said compound isthe (+) enantiomer thereof.
 20. A pharmaceutical composition of claim 18wherein the said compound is the (-) entaniomer.
 21. A pharmaceuticalcomposition of claim 18 wherein the said compound is 1 part (+)enantiomer and 2 to 4 parts (-) enantiomer.
 22. A method of treatment ofedema associated with hypertension comprising the administration of atherapeutically effective amount in unitary dosage form of a compoundhaving the formula of: ##STR11## wherein X is halo, methyl or hydrogen;Yis halo or methyl; R is 2-thienyl, 3-thienyl or 2 or 3 substitutedthienyl wherein the substituent is halo or methyl,a non-toxicpharmaceutically acceptable salt thereof or a lower alkyl esterderivative thereof.
 23. A method of treatment of edema associated withhypertension according to claim 22 comprising the administration to apatient of from 0.01 mg. to 10 mg./kg. of body weight of the patient ofa compound of claim 22 wherein X and Y are both chloro.
 24. A method oftreatment of edema associated with hypertension comprising theadministration to a patient of from 0.01 mg. to 10 mg./kg. of bodyweight of the patent of a compound having the formula: ##STR12## whereinX is chloro;Y is chloro; and R is selected from the group consisting of2-thienyl, 3-thienyl and 5-methyl-2-thienyl,a non-toxic pharmaceuticallyacceptable salt thereof or a lower alkyl ester derivative thereof.
 25. Amethod of treatment of claim 24 wherein the compound to be administeredis 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid.26. A method of treatment of claim 25 wherein the compound to beadministered is the (+) enantiomer.
 27. A method of treatment of claim25 wherein the compound to be administered id the (-) enantiomer.
 28. Amethod of treatment of claim 25 wherein the compound to be administeredis 1 part (+) enantiomer and 2 to 4 parts (-) enantiomer.